Compounds for the treatment of neuromuscular disorders

Abstract

The present invention relates to compounds suitable for treating, ameliorating and/or preventing neuromuscular disorders, including the reversal of drug-induced neuromuscular blockade. The compounds as defined herein preferably inhibit the CIC-1 ion channel.

The invention claimed is: 
     
       1. A compound of Formula (II.2): 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is selected from the group consisting of F, Cl, Br, and I; 
 R 2  is independently selected from the group consisting of hydrogen, deuterium, F, Cl, Br, I, —CN, —CF 3  and -oxime optionally substituted with C 1  alkyl; 
 R 3  is C 1-5  alkyl substituted with one or more substituents R 5 ; 
 R 4  is H; 
 R 5  is independently F; and 
 n is an integer 0, 1 or 2; 
 
         or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. 
       
     
     
       2. The compound according to  claim 1 , wherein
 R 1  is selected from the group consisting of F, Cl, Br, and I; 
 R 3  is C 1-5  alkyl substituted with one or more F; 
 R 4  is H; and 
 n is 0; 
 
       or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. 
     
     
       3. The compound according to  claim 1 , wherein the compound is of Formula (III.2): 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is selected from the group consisting of Cl, Br, and I; 
 R 2  is selected from the group consisting of deuterium, F, Cl, Br, I, and 
 oxime optionally substituted with C 1  alkyl; 
 R 3  is C 1-5  alkyl substituted with one or more F; and 
 R 4  is H; 
 
         or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. 
       
     
     
       4. The compound according to  claim 1 , wherein the compound is of Formula (IV.2): 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is selected from the group consisting of Cl, Br, and I; 
 R 2  is selected from the group consisting of deuterium, F, Cl, Br, and I; 
 R 3  is C 1-5  alkyl substituted with one or more F; and 
 R 4  is H; 
 
         or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. 
       
     
     
       5. The compound according to  claim 1 , wherein the compound is of Formula (V.2) or (VI.2): 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is Br, Cl or I; 
 R 2  is independently deuterium, F, Cl, Br, or I; 
 R 3  is C 1-5  alkyl substituted with one or more F; and 
 R 4  is H; 
 
         or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. 
       
     
     
       6. The compound according to  claim 1 , wherein the compound is selected from the group consisting of:
 (2R)-2-[4-bromo(3,5-H)phenoxy]-3-fluoropropanoic acid; 
 (2R)-2-[4-bromo(2,6-H)phenoxy]-3-fluoropropanoic acid; 
 (2R)-2-(4-bromo-2-fluorophenoxy)-3,3-difluoropropanoic acid; 
 (2R)-2-(4-bromo-2-fluorophenoxy)-3-fluoropropanoic acid; 
 (2R)-2-(2-bromo-4-chlorophenoxy)-3-fluoropropanoic acid; 
 (2R)-2-(4-chlorophenoxy)-3-fluoropropanoic acid; 
 (2R)-2-(4-chloro-2-fluorophenoxy)-3-fluoropropanoic acid; 
 (2R)-2-(2,4-dibromophenoxy)-3-fluoropropanoic acid; and 
 (2R)-2-(4-bromophenoxy)-3-fluoropropanoic acid; 
 or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. 
 
     
     
       7. The compound according to  claim 1 , wherein the compound has the following structure: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. 
       
     
     
       8. A method of treating and/or ameliorating a disorder in a patient by inhibiting a ClC-1 receptor in a patient, comprising administering to a patient in need thereof a compound according to  claim 1  or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof, wherein the disorder is selected from the group consisting of amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), X-linked spinal and bulbar muscular atrophy, Kennedy's disorder, multifocal motor neuropathy, Guillain-Barre syndrome, poliomyelitis, post-polio syndrome, myasthenia gravis, critical illness myopathy (CIM), critical illness polyneuropathy, Charcot-Marie tooth disease (CMT), sarcopenia, Chronic fatigue syndrome (CFS), metabolic myopathy, mitochondrial myopathy, and Lambert-Eaton syndrome. 
     
     
       9. A method of treating and/or ameliorating a neuromuscular disorder in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. 
     
     
       10. A method of reversing and/or ameliorating a neuromuscular blockade in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to  claim 1  or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, or solvate thereof. 
     
     
       11. The method according to  claim 9 , wherein the neuromuscular disorder is myasthenia gravis. 
     
     
       12. The method according to  claim 9 , wherein the neuromuscular disorder is amyotrophic lateral sclerosis (ALS). 
     
     
       13. The method according to  claim 9 , wherein the neuromuscular disorder is spinal muscular atrophy (SMA), critical illness myopathy (CIM), Charcot-Marie tooth disease (CMT) or sarcopenia. 
     
     
       14. The method according to  claim 9 , wherein the neuromuscular disorder has been induced by a neuromuscular blocking agent. 
     
     
       15. The compound according to  claim 1 , wherein:
 R 1  is selected from the group consisting of F, Cl, Br and I; 
 R 2  is independently selected from the group consisting of deuterium, F, Cl, Br and I, and 
 n is an integer 1 or 2. 
 
     
     
       16. The compound of  claim 1 , wherein:
 wherein R 3  is selected from the group consisting of —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CH 2 F, —CH 2 CHF 2  and —CH 2 CF 3 .